This invention relates to trihydroxy polyunsaturated eicosanoid derivatives and methods for the preparation of such compounds and their structural analogs.
The conversion of arachidonic acid (C20:4) to a variety of bioactive eicosanoids, including prostaglandins (PG), leukotrienes (LT) and lipoxins (LX) is well known (Nicolaou, K. C.; Ramphal, J. Y.; Petasis, N. A.; Serhan, C. N. Angew. Chem. Int. Ed. Engl. 1991, 30, 1100).
It was recently reported that endothelial cells upregulated with COX-2 and treated with aspirin, convert eicosapentaenoic acid to a new series of hydroxylated polyunsaturated eicosanoids (Serhan, C. N. etal. J. Exp. Med. 2000. 192, 1197). The present invention provides methods for preparing such lipid mediators, which have potential use in the development of new pharmaceuticals.
It has been suggested that dietary ω-3 polyunsaturated fatty acids (PUFA) (De Caterina, R., Endres, S.; Kristensen, S. D.; Schmidt, E. B., (eds). ω-3 Fatty Acids and Vascular Disease, Springer-Verlag, London. 166 pp. 1993) have beneficial effects in human health and in the prevention of various diseases, including inflammation, cancer (Iigo, M. et al, Br. J. Cancer, 1997, 75, 650) and cardio-vascular diseases (Billman, G. E., et al. Circulation. 1999, 99, 2452). Eicosapentaenoic acid (C20:5), the major PUFA in fish oil, was shown to form prostaglandins (PG), leukotrienes (LT) and other eicosanoids that are similar to those derived from arachidonic acid (C20:4). The different biological properties of these molecules were considered to be responsible for the role of PUFA. Despite numerous studies in this area, however, the molecular mechanisms for the actions of PUFA remain unknown.
It was recently demonstrated (Serhan, C. N. et al. J. Exp. Med. 2000. 192, 1197) that human endothelial cells with upregulated COX-2 treated with aspirin convert ω-3 polyunsaturated fatty acids to 18R-HEPE as well as 15R-HEPE. While 15R-HEPE led to the 5-series lipoxins (15R-LXA5), 18R-HEPE led to 5S,12R,18R-triHEPE (1), a novel trihydroxy-eicosanoid related to the structure of LTB4. In a more recent publication compounds of this type were named Resolvins (Serhan, C. N.; et al, J. Exp. Med. 2002, 196, 1025). The formation of these trihydroxy polyunsaturated eicosanoids from PUFA suggests a novel mechanism for the therapeutic benefits of PUFA with major implications for new therapeutic approaches to a variety of diseases. Methods for the preparation of such compounds, therefore, are of great importance to the development of new therapeutic agents. Furthermore, the development of structural derivatives of these compounds may be useful for the optimization of their pharmacological profile and other desirable drug-like properties.